In:
International Archives of Allergy and Immunology, S. Karger AG, Vol. 159, No. 4 ( 2012), p. 399-409
Abstract:
〈 b 〉 〈 i 〉 Background: 〈 /i 〉 〈 /b 〉 Chronic hypoxia is associated with remodeling in various organs. Reactive oxygen species (ROS) derived from NADPH oxidases (Nox), and transforming growth factor-β 〈 sub 〉 1 〈 /sub 〉 (TGF-β 〈 sub 〉 1 〈 /sub 〉 ) have been implicated in the pathogenesis of hypoxia-induced remodeling. The aims of this study were to determine in hypoxia-stimulated nasal polyp-derived fibroblasts (NPDF) the effect of hypoxia on the differentiation of myofibroblasts, the role of ROS, the major Nox homolog mediating myofibroblast differentiation, and the role of TGF-β 〈 sub 〉 1 〈 /sub 〉 . 〈 b 〉 〈 i 〉 Methods: 〈 /i 〉 〈 /b 〉 Eight primary cultures of NPDF were established from nasal polyps, which were incubated under hypoxic conditions. Reverse transcription polymerase chain reaction for α 〈 i 〉 SMA, Nox1, Nox3, Nox4, Nox5, 〈 /i 〉 and 〈 i 〉 fibronectin 〈 /i 〉 mRNA was performed. Western blotting for α-SMA and fibronectin was done. ROS production was detected using a fluorometer. NPDF were pretreated with ROS scavengers and transfected with 〈 i 〉 siNox4 〈 /i 〉 . The TGF-β 〈 sub 〉 1 〈 /sub 〉 protein level was measured by ELISA. The effect of treatment with TGF-β 〈 sub 〉 1 〈 /sub 〉 type I tyrosine kinase inhibitor SB431542 on myofibroblast differentiation was observed. 〈 b 〉 〈 i 〉 Results: 〈 /i 〉 〈 /b 〉 Hypoxic stimulation of NPDF significantly increased α-SMA and fibronectin mRNA and protein expression. ROS production was increased by hypoxia, and ROS scavengers inhibited myofibroblast differentiation. 〈 i 〉 Nox4 〈 /i 〉 mRNA was the only Nox homolog increased by hypoxia. Transfection with 〈 i 〉 siNox4 〈 /i 〉 inhibited myofibroblast differentiation. TGF-β 〈 sub 〉 1 〈 /sub 〉 was secreted endogenously by hypoxic NPDF. SB431542 significantly inhibited myofibroblast differentiation. 〈 b 〉 〈 i 〉 Conclusions: 〈 /i 〉 〈 /b 〉 Hypoxia induces myofibroblast differentiation of NPDF through a signaling pathway involving Nox4-dependent ROS generation and TGF-β 〈 sub 〉 1 〈 /sub 〉 . Therapies targeting Nox4 may be effective against remodeling of nasal polyps.
Type of Medium:
Online Resource
ISSN:
1018-2438
,
1423-0097
Language:
English
Publisher:
S. Karger AG
Publication Date:
2012
detail.hit.zdb_id:
1482722-0
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